1. Field of the Invention
The present invention relates to the field of treatments for cancer tumors. More particularly, the present invention relates to treatment of cancer tumors with 1,2,4-benzotriazine oxides contained in an encapsulated suspension for oral administration.
2. Reported Developments
Encapsulated suspensions and solutions as carriers of pharmaceutical substances are known in the prior art. For example: U.S. Pat. No. 4,701,327 discloses etoposide soft capsules comprising soft gelatin shells enclosing an etoposide solution therein; European Patent Specification, Publ. No. 0 341,584 B1 discloses a soft capsular preparation comprising sodium picosulfate in a polyethylene glycol solution; and G. B. Patent Application No. 2,229,094A discloses a gelatin capsule consisting of a fatty acid glyceride and/or mineral oil or paraffin as a carrier for ranitidine.
Liquid fill of soft or hard gelatin capsules provide a useful and advantageous means of formulating drug substances and permit incorporation of the active ingredient in the form of a semi-solid, liquid or paste. In most soft gel capsules provided by the prior art, major objects include stability on shelf-life and absorption or bioavailability for efficacy.
In the field of cancer tumor treatment rapid and complete absorption of an anti-cancer drug is of the utmost importance so that a dose/time regiment can be instituted to successfully attack the tumor cells. For example, when increasing the toxicity of chemotherapy agents toward solid tumors is intended, a cytotoxicity enhancing compound is administered to the patient subsequent to which within a certain time-period the chemotherapy agent is administered in order for the drugs to have synergistic affect. Rapid and total absorption of the two drugs enables the practitioner to set the interval times of administration for obtaining maximum efficacy. Parenteral administration is more prevalent of anti-tumor drugs. Such administration is, however, not without pain, inconvenience and the high cost of administration by a practitioner. A convenient oral route of delivery would eliminate these drawbacks in the treatment of cancer tumors.
The present invention has as its objective the provision of a capsule formulated of a 1,2,4-benzotriazine oxide from which the 1,2,4-benzotriazine oxide absorbs rapidly and completely when administered to the patient. In addition, the formulation is stable on shelf-life.
1,2,4-Benzotriazine oxides are known compounds. U.S. Pat. No. 3,980,779 discloses 3-amino-1,2,4-benzotriazine-1,4-di-oxide compositions having the formula ##STR1## wherein one of R and R.sup.1 is hydrogen, halogen, lower alkyl, halo (lower alkyl), lower alkoxy, carbamoyl, sulfonamido, carboxy or carbo (lower alkoxy) and the other of R and R.sup.1 is halogeno, lower alkyl, halo (lower alkyl), lower alkoxy, carbamoyl, sulfonamido, carboxy or carbo (lower alkoxy),
as antimicrobial composition used to promote livestock growth.
U.S. Pat. No. 5,175,287 issued Dec. 29, 1992 discloses the use of 1,2,4-benzotriazine oxides in conjunction with radiation for treatment of tumors. The 1,2,4-benzotriazine oxides sensitize the tumor cells to radiation and make them more amenable to this treatment modality.
Holden et al (1992) "Enhancement of Alkylating Agent Activity by SR-4233 in the FSaIIC Murine Fibrosarcoma" JNCI 84: 187-193 discloses the use of SR-4233, namely 3-amino-1,2,4-benzotriazine-1,4-dioxide, also known and hereinafter sometimes referred to as tirapazamine, in combination with an antitumor alkylating agent. The four antitumor alkylating agents, cisplatin, cyclophosphamide, carmustine and melphalan, were each tested to examine the ability of tirapazamine to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents. Tirapazamine was tested alone and in combination with varying amounts of each of the antitumor alkylating agents. When SR-4233 was administered just before single-dose treatment with cyclophosphamide, carmustine or melphalan marked dose enhancement leading to synergistic cytotoxic effects on tumor cells was observed.
International Application No. PCT/US89/01037 discloses 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. Other related patents include: U.S. Pat. Nos. 3,868,372 and 4,001,410 which disclose the preparation of 1,2,4-benzotriazine oxides; and U.S. Pat. Nos. 3,991,189 and 3,957,799 which disclose derivatives of 1,2,4-benzotriazine oxides.